Microextraction by packed sorbent (MEPS)

Trends in Analytical Chemistry 67 (2015) 34–44

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Trends in Analytical Chemistry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a c

Microextraction by packed sorbent (MEPS) Mohammad Mahdi Moein a, Abbi Abdel-Rehim b, Mohamed Abdel-Rehim a,* a b

Department of Analytical Chemistry, Stockholm University, SE10691 Stockholm, Sweden Faculty of Life Sciences, University of Manchester, Manchester M60 1QD, UK

A R T I C L E

I N F O

Keywords: Automated microextraction Biological sample Drug Environmental analysis Green method Mass spectrometry MEPS Microextraction by packed sorbent On-line coupling Sample preparation

A B S T R A C T

Sample preparation is an important stage in separation and determination of components of interest from complex matrices. Sample preparation strongly influences the reliability and the accuracy of the analysis and the data quality. Recent trends in sample preparation include miniaturization, automation, highthroughput performance, on-line coupling with analytical instruments and low-cost operation using little or no solvent consumption. In the past decade, microextraction by packed sorbent (MEPS) was introduced as a simple, fast, on-line sample-preparation technique. Also, MEPS requires less sample and less solvent. This review gives an outline of the MEPS technique, including fields of application, common formats and sorbents, factors that affect performance, and the major advantages and limitations. Further, we offer and discuss our perspective on the future of MEPS. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2.

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6. 7. 8.

Introduction ........................................................................................................................................................................................................................................................... Microextraction by packed sorbent (MEPS) ............................................................................................................................................................................................... 2.1. Converting solid-phase extraction (SPE) to MEPS ...................................................................................................................................................................... 2.2. Description of MEPS technique ......................................................................................................................................................................................................... 2.3. MEPS format ............................................................................................................................................................................................................................................ 2.4. Various types of sorbents used in MEPS ....................................................................................................................................................................................... 2.5. MEPS as a green method for sample preparation ...................................................................................................................................................................... Automated microextraction by packed sorbent ....................................................................................................................................................................................... 3.1. Use of MEPS off-line and on-line ...................................................................................................................................................................................................... 3.2. Procedure for MEPS syringe ............................................................................................................................................................................................................... 3.3. Features of MEPS ................................................................................................................................................................................................................................... Critical factors in MEPS performance ........................................................................................................................................................................................................... 4.1. Sample loading, washing and elution solutions .......................................................................................................................................................................... 4.2. Sample matrix ......................................................................................................................................................................................................................................... 4.3. Carry-over ................................................................................................................................................................................................................................................ 4.4. Reuse of MEPS sorbent ........................................................................................................................................................................................................................ 4.5. Syringe-to-syringe variations ............................................................................................................................................................................................................ 4.6. Matrix effect in MEPS ........................................................................................................................................................................................................................... MEPS applications ............................................................................................................................................................................................................................................... 5.1. On-line applications of MEPS ............................................................................................................................................................................................................ 5.2. Direct connection of MEPS to mass spectrometry (MS) .......................................................................................................................................................... 5.3. Promising MEPS applications ............................................................................................................................................................................................................ Advantages of MEPS compared with other sample-preparation techniques ................................................................................................................................. Disadvantages of MEPS ..................................................................................................................................................................................................................................... Final remarks and future trends .................................................................................................................................................................................................................... References ..............................................................................................................................................................................................................................................................

* Corresponding author. Tel.: +46 8 163605; Fax: +4687203219. E-mail address: [email protected] (M. Abdel-Rehim). http://dx.doi.org/10.1016/j.trac.2014.12.003 0165-9936/© 2014 Elsevier B.V. All rights reserved.

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1. Introduction It is well known that sample pretreatment is an essential part of analytical and bioanalytical method development and has a significant impact on most of the subsequent steps and the data quality. Since MEPS emerged in 2004 [1], it has been accepted as an attractive option and powerful sample-preparation approach suitable for accomplishing analytical and bioanalytical challenges. This novel technique uses a recognized approach to sample preparation and the pre-concentration of analytes from different matrixes. MEPS is a miniaturized form of the solid-phase extraction (SPE) technique, namely the purification or speciation of samples, but with some significant differences. In MEPS, compared with SPE, the packing is integrated directly into the syringe and not in a separate column. Hence, there is no need for a separate robot to apply the sample into the solid phase, as in SPE. MEPS can even be used more than 100 times for plasma or urine samples, but a conventional SPE column is used only once. MEPS can handle small volumes of sample (10 μL of plasma, urine or water) and large volumes (1000 μL), and can be connected on-line to gas chromatography (GC), liquid chromatography (LC), LC coupled to mass spectrometry (LC-MS), GC-MS or capillary electrochromatography (CEC). MEPS is a flexible approach to sample preparation in reversed phases, normal phases, mixed mode or ion-exchange chemistries. MEPS can be fully automated, including the sample-processing, extraction and injection steps, as an on-line sampling device using the same syringe [2]. 2. Microextraction by packed sorbent (MEPS) 2.1. Converting solid-phase extraction (SPE) to MEPS MEPS uses the same sorbents as conventional SPE columns. Unlike conventional SPE columns, the MEPS sorbent bed is integrated into a liquid-handling syringe that allows for low-void-volume sample manipulations manually or with laboratory robotics. When the sample has passed through the solid support, the analytes are adsorbed onto the solid phase packed in the barrel insert and needle

35

(BIN). MEPS is suitable for use with most existing SPE methods by scaling down the reagent and sample volumes. Because both MEPS and SPE build on the same principles and are quite robust, transferring a method from traditional SPE to MEPS would be relatively straightforward. The difference between MEPS and SPE is that, in SPE, the solution flow is in one direction (up to down) but in MEPS it is in two directions (up and down) [2], so the optimization of washing and elution steps is important. 2.2. Description of MEPS technique In MEPS, ~2 mg of the solid-packing sorbent is packed inside a syringe (100–250 μL) as a plug or between the barrel and the needle as a cartridge, as shown in Fig. 1. Sample extraction and enrichment can be accomplished on the packed sorbent. This technique combines sample extraction, pre-concentration and clean-up in a single device composed of the following two parts: the MEPS syringe and the MEPS cartridge, also known as the BIN. The BIN contains the packed MEPS bed, a solid support that retains the target analytes when the sample passes through it and is built into the syringe needle. The BIN is used with a 100-μL or 250-μL gas-tight MEPS syringe that allows fluid handling at normal SPE pressures. When the BIN is exhausted, or another phase is required, the BIN is easily exchanged by simply unscrewing the locking nut and removing then replacing the BIN. The full device can be operated in different ways, from manually to on-line. The MEPS approach to sample preparation is suitable for reversed phases, normal phases, mixed mode or ion-exchange chemistries. In general, MEPS is an adaptation of SPE that incorporates all the desirable characteristics into a miniaturized device with a typical void volume of less than 10 μL. This, combined with its compatibility with autosampler syringes, makes the MEPS format ideal for a digital LC-elution GC approach to analysis. 2.3. MEPS format MEPS is a lab-in-syringe and the typical MEPS is designed in syringe format. A gas-tight glass syringe is used; the syringe volume

Fig. 1. Syringe for microextraction by packed sorbent (MEPS) with packing bed (the dead volume is about 7 μL).

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M.M. Moein et al./Trends in Analytical Chemistry 67 (2015) 34–44

2.5. MEPS as a green method for sample preparation There are numerous advantages for MEPS compared to SPE. The most important advantage is the small volume of solvent and small amount of packing material needed. Reducing solvent and chemical waste is a major target for greener bioanalysis. In MEPS, a small amount of sorbent (1–2 mg) is used and the sorbent bed can be reused up to 100 times. Thus, MEPS is an environment-friendly sample-preparation technique because of the small amount of sorbent used and the small volumes of solvent required (from mL to μL; SPE to MEP) [98]. 3. Automated microextraction by packed sorbent 3.1. Use of MEPS off-line and on-line

Fig. 2. Developments in microextraction by packed sorbent (MEPS).

is 100 μL, 250 μL or 500 μL. The sorbent may be accommodated in a small container situated between the barrel and the needle (Fig. 1). The importance of this approach is that it makes it possible to fully integrate the sample preparation with the analytical system. Thereby, automation of the entire analysis system becomes straightforward. MEPS can be used on-line with GC, LC, or MS without any modification of the instrument. A further key point is that only a small amount of sorbent is used (miniaturization), so only relatively small amounts of solvents are needed for elution of the analytes from the adsorbent – a quantity suitable for direct introduction into the analysis instrument. Over the past decade, the MEPS format has improved from manually (inside a syringe or BIN) to semi-automated and fully automated (Fig. 2) and these developments can promote operation of this technique in the near future.

2.4. Various types of sorbents used in MEPS One of the most important parts of MEPS is the sorbent. As apparent in Table 1, most of the sorbents that have been used are silica-based sorbents (C2, C8 and C18). Also, polyester polymerbased sorbents have attracted the interest of many research groups. The lack of selectivity is the main problem with the use of common sorbents in MEPS. To overcome this problem, molecularly-imprinted polymers (MIPs) with highly specific recognition abilities for target molecules were found to be appropriate [27,33,62]. Also, the use of polypyrrole or polyamide electrospun-based sorbents in MEPS has created a new approach, which was successfully used for separating pesticides from aquatic samples [48]. In another work, a polyaniline (PANI) nanowire network was synthesized and used as a sorbent in MEPS for the multiresidue determination of selected analytes from triazine, organochlorine and organophosphorus pesticides in aqueous samples [57]. A special type of non-porous carbon is another sorbent that has been used in MEPS for the extraction of rosmarinic acid [71]. The results of this work showed that CMK-3 non-porous carbon is an appropriate, efficient sorbent for MEPS. Recently, some new sorbents for MEPS were prepared in AbdelRehim’s group to be more effective, durable and easy to use, such as carbon-based materials, needle-trap MIP-sol-gel, membrane modified by MIP-sol-gel and MIP-sol-gel electrospun sorbents [96,97].

Commercially, MEPS is available in a variety of common SPE phases [99]. MEPS uses the same sorbents as conventional SPE columns, so it is suitable for use with most existing methods by scaling the reagent and sample volumes. Unlike conventional SPE columns, the MEPS sorbent bed is integrated into a liquid-handling syringe that allows for low-void-volume sample manipulations manually or with laboratory robotics. When the sample has passed through the solid support, the analytes are adsorbed onto the solid phase packed in a barrel insert and needle (BIN) [98]. This makes it simple to integrate the sample preparation fully with other parts of the analysis system, and automation of the entire analysis system becomes straightforward. Because a small amount of sorbent is used, only relatively small amounts of solvents are needed for the elution of the analytes from the adsorbent. The advantages of MEPS are as follows:

• • • • •

it is fully automated; it provides a reduced total analysis time; small sample volumes are used; it facilitates the enrichment of the analytes; and, it is simple and inexpensive.

MEPS allows sparing use of sample and reagents, but a more significant strength of MEPS is the ability to elute the sorbent fully with volumes of 10–50 μL through a needle, using controlled flow rate. Such capability allows MEPS to be adapted for on-line use with GC and LC inlets or in 96-well-plate format for use with immunoassay and other colorimetric techniques. In addition, in some samplepreparation techniques, such as liquid-liquid extraction (LLE), pre-concentration of the eluted sample by solvent evaporization, especially in environmental analysis, is a significant source of errors. Whereas MEPS has a huge concentration factor, a low elution volume (10–100 μL) is needed to elute the analyte from the solid bed, so, ideally, the appropriate concentration factor for the target analytes should be obtained in minimum loading cycles of sample volume. However, MEPS protocols usually use several extraction cycles (up to 10 or more). This creates another optimization opportunity as, when the sample is loaded several times, the aliquot can be discarded or reloaded several times. The selection of the best condition depends on the nature of the matrix being used and the retention capacity and specificity of the sorbent. The best methodology does not necessarily present higher recoveries of the target analytes if too many interferences are also retained [3]. 3.2. Procedure for MEPS syringe The sample is drawn once or more through the sorbent manually or by an autosampler (draw–eject in the same vial or draw and eject into waste). When the sample has passed through the solid

M.M. Moein et al./Trends in Analytical Chemistry 67 (2015) 34–44

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Table 1 Applications of microextraction by packed sorbent (MEPS) Analyte Lidocaine, mepivacaine, bupivacaine, ropivacaine Sarcosine Local anesthetics Roscovitine Olomoucine Ropivacaine, lidocaine, metabolites (glycylxylidide, monoethylglycylxylidide, and 3-OH-lidocaine) Acebutolol, metoprolol Methadone Cyclophosphamide AZD3409 Bupivacaine and [d3]-Mepivacaine Fluoroquinolones Cocaine and Its Metabolites Anesthetic drugs Methamphetamine and amphetamine Dissolved organic matter and natural organic matter Metabolites of monoterpenes Organic priority pollutants and emerging compounds Antidepressants Risperidone and its metabolite UV filter and polycyclic musk compounds Oxcarbazepine and its metabolites Cotinine Steroid metabolites Risperidone and 9-hydroxyrisperidone Fluoroquinolone-related compounds Non-polar heterocyclic amines Remifentanil Clozapine and its metabolites Atorvastatin and its metabolites Clofibric acid, ibuprofen, naproxen, diclofenac and ketoprofen Estrogenic compounds

MEPS sorbent

Ref.

GC-MS

[1]

MIP Benzenesulphonic acid cation exchange silica based Polystyrene polymer, ISOLUTE ENV+ Polystyrene polymer Silica-based (C8), polymer-based (ENV+), and a methacrylate-based organic monolith Polystyrene polymer Csilica-C8 C2-sorbent C2, C8, and polystyrene polymer C18 and hydroxylated polystyrenedivinylbenzene copolymer (ENV+) C18 C8 , ENV+ ,Oasis MCX, Clean Screen DAU C18 C18 C18

Human plasma and urine Human plasma

LC–MS/MS LC–MS/MS

[3] [4]

Plasma and urine Human plasma Plasma and urine

LC–MS/MS LC–MS/MS LC–MS/MS

[5] [6] [7]

Plasma and urine Plasma and urine Patients plasma Rat, dog, and human plasma samples Plasma samples

LC–MS/MS GC/MS LC–MS/MS LC–MS/MS LC–MS/MS

[8] [9] [10] [11] [12]

Urine Human urine Human plasma In hair River water marine samples

CE-MS MS-TOF CE-MS MiAMi–GC/MS FT-ICR-MS

[13] [14] [15] [16] [17]

C18 Silica gel sorbents modified with C18

Human urine Wastewater and snow samples

GC/MS GC/MS

[18] [19]

C8 C8 C8 and C18 C18 C2, C8, C18, silica, and C8/SCX C18 C8 MIP C18 C8

Human plasma Plasma and saliva Water samples Plasma and saliva Human urine Animal urine Human plasma, urine and saliva Water Urine Human plasma Dried blood spots Serum obtained From patients Water samples

LC-UV LC with coulometric detection GC-MS LC-DAD GC–MS GC–MS LC-UV LC–MS/MS μLC-fluorimetric detection LC–MS/MS LC- Coulometric detection UHPLC-MS/MS

[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31]

PTV–GC–MS

[32]

Water samples

GC–MS

[33]

In heroin addicted Patients plasma Wine Dried blood-spot specimens from patients undergoing methadonemaintenance treatment. Human Plasma and Groundwater

LC-CD

[34]

UPLC-PDA LC- coulometric detection

[35] [36]

LC-UV

[37]

GC–MS LC–MS/MS UPLC-PDA LC-DAD LC-DAD Micro-capillary array electrospray ionization MS UHPLC–MS/MS GC–MS LC-UV

[38] [39] [40] [41] [42] [43]

CE GC–MS GC–MS UPLC-DAD GC-MS, LC-MS

[47] [48] [49] [50] [51]

GC-MS GC-MS GC-MS GC–μECD GC-MS GC-MS

[52] [53] [54] [55] [56] [57]

C8 C18

Opioids (E)-resveratrol Methadone

C2, C8, C18, SIL, and M1 C18

1,3,5-Trinitroperhydro-1,3,5-triazine and 2,4,6-Trinitrotoluene Polycyclic aromatic hydrocarbons Immunosuppressive drugs, Phenolic constituents of biological interest Piperazine-type stimulants Psychotropic drugs Propranolol, metoprolol, verapamil

C18

Ionic liquids Organophosphorus pesticides Volatile and semi-volatile constituents Piperazine-type stimulants Sensory neuron-specific receptors agonist BAM8-22 and antagonist BAM22-8 Macrocyclic musk fragrances Polycyclic aromatic hydrocarbon Antiepileptic drugs Haloanisoles Aromatic amines Pesticides

Method

Human plasma

17β-Estradiol-molecularly imprinted polymer (MIP) and silica gel (modified with C-18) C8

Pravastatin and pravastatin lactone Phenolic acids Antiepileptic drugs

Matrix

C18

C18 C8 C2, C8, C18, SIL, and M1 C18 C18, C8, and C8-SCX C2, C8, C18, M1 (cation exchanger), and Sil (pure silica) C8 C18 C18

Water Whole blood Wines Human urine Human serum Urine

Silica Polypyrrole/polyamide C2, C8, C18, Silica and M1 (mixed C8-SCX) C8 and C18 C2, C8 and ENV+

Rat plasma and urine Plasma Human Plasma and urine River water Aquatic samples Wines Human urine Plasma

C18 C8 C18 C18 C18 Polyaniline nanowires

Wastewater Water Human plasma and urine Wines Environmental water samples Aquatic media

[44] [45] [46]

(continued on next page)

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Table 1 (continued) Analyte Flavonols Melatonin and other antioxidants L-ascorbic acid determination

Haloacetic acids Local anesthetics: lidocaine, ropivacaine, mepivacaine and bupivacaine Cardiac drugs in Serotonin Reuptake Inhibitor Antidepressants Musk ketone Lidocaine Nonsteroidal anti-inflammatory drugs Phenyl flavonoids Cannabinoids Chlorobenzenes Rosmarinic acid Oxidative stress biomarkers Olive biophenols Antipsychotic drugs Polycyclic and nitro musks Urinary biomarkers of oxidativelydamaged DNA Antipsychotic drugs Hydroxybenzoic and hydroxycinnamic acids Antipsychotic ziprasidone Acortisol, cortisone and corticosterone Entecavir Ractopamine Aromatic amines formed Ethyl carbamate Β-blocker, metoprolol and acebutolol Polycyclic aromatic hydrocarbons Bupivacaine; lidocaine; ropivacaine Haloacetic acids Tricyclic antidepressant drugs Chlorophenols Brominated diphenyl ethers Non-steroidal anti-inflammatory drugs Clenbuterol carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin and the active metabolites carbamazepine-10,11-epoxide and licarbazepine Cepharanthine Sulfonamids

Method

Ref.

C2, C8, C18, SIL, and C8/SCX C8 Containing silica, C2, C8, C18 and Silica with C8 labelled as M1 C18 MIP

MEPS sorbent Wines Foodstuffs Beverages

UHPLC-DAD LC- fluorescence LC-UV

[58] [59] [60]

Chlorinated water Plasma and urine samples

GC-MS LC-MS/MS

[61] [62]

C8 C8 and strong cationic exchange sorbent C18

Human urine Plasma sample

UHPLC-MS/MS Non-Aqueous CE

[63] [64]

River water samples.

[65]

C8 C18 C2, C8, C18, SIL, and M1 C18 C18 CMK-3 nanoporous carbon C2,C8,C18,SIL (silica) and M1(mix of C8 plus SCX – strong cation exchanger) CMK-3 nanoporous sorbent 80%C8 and 20%SCX C18 C8

Human saliva Human urine Beers Oral fluids Water samples Aqueous Health and patient urine samples

Surface-enhanced Raman spectroscopy (SERS) LC-MS/MS UHPLC-UV UHPLC-DAD LC-MS/MS GC-MS LC-UV UHPLC-PDA

Rat plasma Human plasma Environmental water Urine

LC-UV GC-MS/MS LVI-GC–MS LC-PDA

[73] [74] [75] [76]

C18 C2, C8, C18, SIL and C8/SCX

Human plasma Wines

GC-MS LC-PDA

[74] [77]

C2 C8

LC-UV LC-DAD

[78] [79]

Porous graphitic carbon particles C18 and C8/SCX, 8 μL BIN volume DVB SIL, C2, C8, C18, and M1 Polystyrene C8 C18 C18 C8/SCX C18 C18 C18 MIP C18

Human plasma Saliva, plasma, blood and urine samples Plasma and plasma ultrafiltrate Porcine muscle and urine samples Azo dyes in textiles Fortified wines Human plasma and urine Water Human blood Chlorinated water Human oral fluid Soil samples Sewage sludge Human plasma and urine Pork samples Human plasma

LC-MS/MS LC-UV GC–MS GC–MS LC-MS/MS GC-MS LC-MS/MS GC-MS UHPLC–MS GC-MS GC-MS HPLC-PDA HPLC HPLC-DAD

[80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93]

C8 C8

Human plasma Poultry litter wastewater samples

UPLC HPLC

[94] [95]

support, the analytes have been adsorbed to the solid phase. The solid phase is then washed once by 50–100 μL water to remove the interferences. The analytes are then eluted with a solvent (20– 50 μL) directly into the injector of the instrument. The process can be manual, semi-automated or fully automated. To reuse a MEPS cartridge, the sorbent is washed 3–4 times with water and 4–5 times with elution-solution solvent to eliminate carry-over. Due to the smaller amount of the sorbent, sorbent conditioning and drying steps are as unnecessary in MEPS as they are in SPE. MEPS can be regarded as a pre-column in a syringe and the MEPS sorbent can be reused for about 100 extractions without any loss in performance. Concerning plasma samples, the quality of plasma is important for the lifetime of the MEPS. If the plasma sample is centrifuged, MEPS can be reused up to 100 times without any loss in performance. For non-centrifuged plasma, we observed that the MEPS performance became worse after 40–50 extractions. In the same way as all packed columns, the MEPS silica bed is damaged if a sample of extreme pH is loaded.

Matrix

[66] [67] [68] [69] [70] [71] [72]

3.3. Features of MEPS Single-use MEPS cartridges were developed to eliminate carryover occurrences. This new single-MEPS (brand name: SPEed and SPEmx) is produced for use only once and is fully automated. In a single-use MEPS cartridge, there are two flow paths – one for aspiration of liquids (sample or solvents) into the syringe barrel directly and the second for dispensing through the sorbent bed. The analytes can therefore be focused on the top of the sorbent bed, giving a high concentration factor (www.eprep.com.au). In common conventional MEPS, the particle size is 30–50 μm; in single-use MEPS, the particle size is smaller (3 μm). Also, two flow channels are used – one for aspirating and one for dispensing –and that approach can help to prevent carry-over and to facilitate aspirating the solutions and samples through the solid bed. MEPS has been commercialized by SGE (SGE Analytical Science Pty Ltd, Victoria, Australia). The MEPS syringe and the MEPS BIN can be obtained from many suppliers, such as ThermoFisher

M.M. Moein et al./Trends in Analytical Chemistry 67 (2015) 34–44

Scientific Inc. (Madison, WI, USA), and VWR International in many countries. 4. Critical factors in MEPS performance In this section several significant effective parameters in MEPS will be considered and highlighted. 4.1. Sample loading, washing and elution solutions The most important parameters in MEPS performance can be divided into the following four main categories: (1) choosing a solvent for the conditioning, loading, washing and elution sections; (2) sample flow rate; (3) washing solution; and, (4) elution solvent, type and volume. MEPS has four main steps, which include conditioning, sampling, washing and elution, which are shown in the schematic of the MEPS process in Fig. 3. Beginning with the solvents and sample flow, which can affect all of the steps of MEPS protocols to more or less of a degree depending on which device is being used to control the extraction, these parameters can be accurately controlled to modulate the interaction of the target analyte with the sorbent. Apparently, a lower flow allows a better interaction between the analyte and the sorbent. This is, however, a drawback in the case of manual MEPS extraction, as the flow is not measured and the repetitive handling procedure is user-dependent and prone to experimental errors. In the first step of the MEPS process, the sorbent conditioning, the volumes of the solvents and the loading cycles used should be optimized to avoid carryover from the previous extractions. Usually, two volumes of the total syringe capacity are recommended, starting with a strong organic solvent and following that an equilibration with water that can eventually be acidified. Samples can be loaded directly or properly diluted if they are too viscous or concentrated. This is the case

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for biological fluids that most often are pretreated by dilution, protein precipitation, centrifugation and/or additional techniques [100] before being loaded into the MEPS device. Additionally, this procedure also allows very abundant compounds that could easily saturate the sorbent and limit the MEPS extraction efficiency to be discarded. The sample volume used should be optimized to obtain the best equilibrium between a good analytical performance and a good extraction methodology. Therefore, ideally the proper concentration factor for the target analytes should be obtained in the minimum sample volume loading cycles, but it is not unusual to observe MEPS extraction protocols using up to ten or more extraction cycles. This creates another optimization opportunity when the sample is loaded several times; the aliquot can be discarded or reloaded several times. The selection of the best conditions will depend on the nature of the matrix being used and the retention capacity and specificity of the sorbent. The best methodology is not necessarily the one that presents the highest recoveries of the target analytes if too many interfering compounds are also retained. The washing step is intended to discard analytes that were nonspecifically retained in the sorbent, thereby improving the enrichment factor of the target analytes. The washing step is usually performed with the same solvent used to equilibrate the sorbent in the first step, but once again, further optimization of the number and the volume of the washing cycles should be assayed. Finally, the elution step should also be critically optimized to allow the release of the analytes from the sorbent in a suitable solvent and volume for injection into LC or GC systems. Overall, the simpler extraction procedure, with the lowest number of operations, will be the most desirable as it will certainly be faster and will limit the introduction of experimental errors into the final analytical performance. 4.2. Sample matrix Sample matrix has an important influence on MEPS performance when complex matrices such as plasma, blood and urine are used. The plasma or urine samples must be diluted at least 1:4 by water, and, for whole blood the dilution is 20 times. The plasma or blood sample is drawn through the sorbent by an autosampler

Fig. 3. Microextraction by packed sorbent (MEPS) (in which the process is fully automated).

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(draw–eject in the same vial or draw and eject into waste). The sample can be drawn once or more if the pre-concentration of the analytes is required. 4.3. Carry-over The carry-over is a well-known problem in bioanalysis. The small amount used in MEPS cartridge can be easily and effectively washed between injections to reduce the possibility of carry-over. This washing process is simply MEPS and not practical with off-line SPE devices. With automation of MEPS, washing can occur while the previous sample is running. In some studies, the carry-over decreased to less than 0.02% when the sorbent was washed at least four times with elution solution and washing solution between extractions [2]. 4.4. Reuse of MEPS sorbent The carry-over in MEPS has been reported to be less than 0.1% with 4–5 washes of methanol prior to reuse [12]. Carryover from the sorbent can be reduced further by adding additional conditioning rinses to the method. The number of reuses possible for a MEPS cartridge is dependent on the sample matrix. As with conventional SPE, maintaining functional flow during the lifetime of the device is matrix dependent. For samples loaded with extreme pH, the MEPS bed will be damaged in the same way as all packed columns. For the extraction of plasma samples and human urine, reversedphase MEPS devices have been used for in excess of 100 injections and for more than 300 injections for water samples [84,101]. 4.5. Syringe-to-syringe variations The reproducibility of MEPS measurements showed good RSD% values for analyte recovery for different analytes and different matrices. Syringe-to-syringe variations were also tested. It was reported that the variations between three different MEPS cartridges, using ropivacaine in human-plasma samples, were similar (variation 1–10%) in terms of accuracy and precision for the all the syringes studied [2]. 4.6. Matrix effect in MEPS Matrix effect is a well-known problem in electrospray-ionization MS (ESI-MS) regarding ion suppression of complex matrices, such as blood, plasma and urine. The presence of salts, phospholipids and proteins is probably the main reason for ion suppression [102]. In MEPS, controlling some factors, such as sort and particle size of the solid phase, and washing and eluting solutions, can assist in reducing or preventing the matrix effect. Utilizing 10% isopropyl in washing can especially assist in eliminating interfering compounds and reducing carry-over. Also, using 2–5 times washing solution between each run can reduce carry-over in MEPS. 5. MEPS applications MEPS has been employed for the analysis of drugs, pesticides, polycyclic aromatic hydrocarbons and other organic pollutants in environmental water samples. Moreover, it has also been successfully applied to the qualitative and quantitative determination of a wide variety of drugs and metabolites in biological samples, such as plasma, serum, blood, urine, saliva and hair. MEPS could be of interest in a variety of areas, including clinical, pharmaceutical, forensic, toxicological, food and flavor, and environmental research [1,2,4–95,98–101]. Table 1 gives a complete list of works in which MEPS has been used along with precise information. The merit of each sample-preparation technique becomes apparent when applied

in complex environments. MEPS has already been used as a sample-preparation method in biological fluids in many research studies because of its speed, sensitivity and selectivity. As shown in Table 1, the extraction of analytes from biological fluids, such as human and animal plasma, urine and saliva, has been the common main issue in using MEPS. Environmental samples are another interesting media for which the application of MEPS has quickly increased. Moreover, some food-analysis and textile studies used MEPS for sample preparation, indicating that MEPS could be used for many varieties of sample. 5.1. On-line applications of MEPS Finding ways to couple MEPS on-line with analytical chemistry instruments is a critical issue that can help utilization of this technique in different fields. Some on-line works were developed recently, such as the analysis of cyclophosphamide in plasma samples of patients [10], local anesthetics in human-plasma samples [4] by LC-MS/MS, cocaine and its metabolites in human-urine samples by direct analysis in real-time coupled to time-of-flight MS (TOFMS) [14], and local anesthetics in human-plasma samples using GC-MS [1]. 5.2. Direct connection of MEPS to mass spectrometry (MS) As a flexible sample-preparation method, MEPS can be used for direct connection to MS and a few works have been published with this approach. MEPS was directly connected to a TOF mass spectrometer and used for detection of drugs of abuse in human-urine samples [14]. In this study, utilizing a robotic auto-sampler and interfacing it with direct analysis in a real-time (DART) TOF mass spectrometer created a fully automated method. In another novel approach, a controlled directional flow (CDF) MEPS was coupled directly to ESI-MS and applied to screening of opiates and codeine metabolites in urine samples [103]. In this work, a digital analytical syringe was applied to control flow and drive the speed of the method, which was fast (less than 5 min), reduced the carry-over from 65% in a conventional MEPS method to 1%, and was sensitive. Recently, MEPS was coupled to ESI-MS/MS to determine amphetamine and methadone in human-urine samples [104]. This rapid, cost-effective method was an effective option in clinical and forensic analysis. However, coupling MEPS to MS systems needs more investigation and consideration in the near future. 5.3. Promising MEPS applications Molecularly-imprinted polymers (MIPs) are becoming increasing popular because they are easy to prepare and their use as sorbents will improve the analytical performance in critical applications, mainly because MIPs act as artificial antibodies, therefore binding with high specificity the target analytes without being affected by the drawbacks of their biological counterparts. Utilization of custom MIPs as MEPS sorbents {MIMEPS, as described in Pereira et al. [99]} has already been explored in several reports. Möder and collaborators reported the use of custommade MEPS BINs packed with MIPs for different wastewater contaminants [19,27,33], and Daryanavard et al. [62] use the same approach to analyze different anesthetics in plasma and urine. In another report, carbon nanotubes have been combined with MEPS extraction followed by capillary electrophoresis to allow the analysis of trace levels of ionic liquids in river-water samples [47]. New materials presenting innovative properties are continuously being developed and their use in MEPS extraction will be certainly explored to raise the analytical limits of different methods even more.

M.M. Moein et al./Trends in Analytical Chemistry 67 (2015) 34–44

In this sense, multi-walled carbon nanotubes and graphene are two very promising candidates [57]. Recently, an on-line separation of prostate-cancer biomarkers by MIP-MEPS coupled to LC-MS/MS from biological fluids was developed by Abdel-Rehim’s group [96,97,104–106]. It seems the future of MEPS is in finding new ways for on-line coupling of MEPS to analytical chemistry instruments [84]. In another application, Rahimi et al. described utilization of CMK-3 nanoporous carbon as an efficient sorbent for MEPS extraction of rosmarinic acid in Rosmarinus officinalis L. (rosemary). This polyphenol is mainly responsible for the potent antioxidant properties of this herb, which is widely used to increase the shelf-life of foods [71]. 6. Advantages of MEPS compared with other sample-preparation techniques MEPS is one of the simplest sample-extraction techniques and presents several advantages when compared with other samplepreparation techniques. MEPS not only retains the major successful features from SPE, namely its broad applications and simplicity, it also improves the analytical performance that can be obtained with various ranges of analytes and matrixes. This improvement was achieved through miniaturization of all the procedures, particularly the solvent requirements and the amount and the presentation of the sorbent, which is limited to a few milligrams (1–4 mg) and is packed in a small cylinder through which the sample is drawn several times. MEPS is therefore much more environment-friendly then SPE and other extraction techniques, such as LLE. Also, although sample requirements for a proper extraction are highly variable, with MEPS, these volumes are greatly reduced, and that can be extremely important in the analysis of precious samples, such as biological ones whose collection is invasive and painful, which produce limited volumes of sample. Unlike other techniques, MEPS can reuse sorbents many times, up to 100 or more, depending on the complexity of the matrix being processed, so the cost per analysis is much lower than could be obtained using SPE, for example. MEPS utilization is very easy and straightforward. MEPS is also very economical and user-friendly. Finally, MEPS is faster than other sample-extraction procedures, as each step is performed faster, mostly using an automatic autosampler, and the target analytes are eluted in a suitable volume without the need for concentration steps usually associated with analyte losses. Table 2 gives a brief comparison between various sample-preparation methods. 7. Disadvantages of MEPS Although MEPS has several advantages, similar to other samplepreparation methods, it also has some disadvantages. MEPS presents some limitations, as the packed sorbent sealed inside the BIN can

41

be easily clogged and unable to be utilized if viscous or highly concentrated samples are used without previous dilution. To overcome the possibility of blocking the BIN, prior sample deproteinization using methanol or acetonitrile is performed in many applications. Dilution of the samples is another way to solve this problem. This procedure has the additional advantage of increased sorbent reusability. In a similar way, MEPS is not very suitable for processing largevolume samples because only up to 500 μL can be loaded each time, so to process, e.g., a 10-mL sample, the sample would have to be loaded at least 20 times, making the entire procedure too long and laborious, even for semi-automatic and automatic versions. Moreover, a 10-mL sample would also strongly affect the reusability of the sorbent, which is one of the main advantages of MEPS. Regarding this aspect, we have to assess carry-over effects carefully. Usually, they are minimized by introducing two or more cycles of sorbent washing and reconditioning between samples. Another MEPS limitation is the range of sorbents available. However, this limitation is gradually being improved as MEPS becomes more popular, with the introduction of polymeric phases. Nonetheless, a major breakthrough for MEPS utilization and analytical performance would certainly be the possibility of having commercial sorbents tailored for applications of interest, as MIPs sorbents, rather than as generic sorbents, in which unspecific analytes and interferences are often co-eluted and several optimization steps have to be performed to minimize this limitation. 8. Final remarks and future trends The application of MEPS as a miniaturized type of SPE is growing fast for biological samples. The extraction of diverse analytes, such as drugs, metabolites, and pesticides, from biological fluids and aqueous samples has been investigated by the MEPS technique. The high sensitivity, ease of use, fast speed, reduced solvent usage and ease of on-line application make MEPS a good candidate for future growth in the area of sample preparation. The following goals seem to be critically important for the further development MEPS: (1) preparing and using new sorbents with more porosity, greater stability, long lifetime and chemical thermal stability, such as MIP sol-gels, carbon-based sorbents and nanomaterials; (2) utilizing MEPS for the extraction of important analytes, such as cancer biomarkers from biological fluids; (3) simplification of the on-line coupling of MEPS with LC-MS or GC-MS instruments; and, (4) developing single-use MEPS and make it easy to change the MEPS cartridge after each run, which could help to decrease several disadvantages of MEPS. To achieve all of these goals, requires more investigation and examination by various academic and industrial groups.

Table 2 Comparison of common sample-preparation techniques Method

Sample volume (mL)

SPE

≤1

SPME SBSE MEPS

0.5–20 1–100 0.01–0.1

Extraction time (min)

Multiple step

10–15

Yes

10–20

One step adsorption/ desorption One step adsorption/ desorption Yes

10–60 1–4

Advantages High Sorptive capacity, chemical or physical mechanical Stability, high selectivity Solvent free, online, suitable for volatile compounds High sensitivity, high extraction recovery, packed and coated sorbent High throughout, sensitivity, fast and easy, good extraction recovery

Disadvantages Large volume of solvent, time consuming Losing and breakable fiber, desorption, low sensitivity Coating loss, Drying and desorption, on line disability, long equilibrium time Blockage and Carryover Desorption

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Finally, the use of MEPS on-line directly with MS for fast screening and quantification of drugs in biological fluids should be one of most interesting applications in the future.

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